JP2005529182A5

JP2005529182A5 -

Info

Publication number: JP2005529182A5
Application number: JP2004513243A
Authority: JP
Filing date: 2003-06-02
Publication date: 2006-07-06
Anticipated expiration: 2023-06-02

Claims

Formula I

Fluorinated cycloalkyl derivatized benzoylguanidines, and pharmacologically acceptable salts thereof.
In the above formula,
X is oxygen, sulfur or NR6;
R6 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or (CH ₂₎ _k -CF ₃
Is;
k is 0, 1, 2 or 3;
m is 0, 1, 2 or 3;
n is 0, 1, 2 or 3;
p is 0, 1, 2 or 3;
q is 1, 2 or 3;
r is 0, 1, 2 or 3;
In this case, the sum of m, n, p, q and r is at least 2;
R1 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, -OR (7),
-NR (8) it is R (9) or -C _s F _{2s + 1;}
R (7), R (8 ) and R (9) independently of one another are hydrogen, alkyl or (CH ₂₎ _t -CF ₃ having 1, 2 or 3 carbon atoms;
s is 1, 2, 3 or 4;
t is 0, 1, 2, 3 or 4;
R2 is alkyl having hydrogen, F, Cl, 1, 2, 3 or 4 carbon atoms, or a CF _3;
R3 hydrogen, F, Cl, alkyl having 1, 2, 3 or 4 carbon atoms, be CF ₃ or SO _u R10;
u is 0, 1 or 2;
R10 is alkyl having 1, 2, 3 or 4 carbon atoms, or NR11R12;
R11 and R12 are independently of one another hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
R4 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, -OR (13 ), - NR (14) be R (15) or -C _v F _{2v + 1;}
R (13), be R (14) and R (15) alkyl or (CH ₂₎ _w -CF ₃ having independently of one another are hydrogen, a 1, 2 or 3 carbon atoms;
v is 1, 2, 3 or 4;
w is 0, 1, 2, 3 or 4;
R5 is hydrogen or F.

X is oxygen, sulfur or NR6;
R6 is hydrogen, methyl or CH ₂ -CF _3;
m is 0, 1 or 2;
n is 0, 1 or 2;
p is 0, 1 or 2;
q is 1 or 2;
r is 0, 1 or 2;
In this case, the sum of m, n, p, q and r is at least 2;
R1 is hydrogen, methyl, F, Cl, -OR (7 ), - NR (8) R (9) or be -CF _3;
R (7), R (8 ) and R (9) independently of one another are hydrogen, methyl, in CF ₃ or CH ₂ -CF _3;
R2 hydrogen, F, Cl, methyl or CF _3;
R3 hydrogen, F, Cl, alkyl having 1, 2, 3 or 4 carbon atoms, be CF _{_3,} SO ₂ CH ₃ or SO ₂ NH _2;
R4 is hydrogen, methyl, F, Cl, -OR (13 ), - NR (14) be R (15) or -CF _3;
R (13), R (14 ) and R (15) independently of one another are hydrogen, methyl, in CF ₃ or CH ₂ -CF _3;
2. A compound of formula I as defined in claim 1 wherein R5 is hydrogen or F, and pharmaceutically acceptable salts thereof.

X is oxygen, sulfur or NR6;
R6 is hydrogen, methyl or CH ₂ -CF _3;
m is 0 or 1;
n is 0, 1 or 2;
p is 0 or 1;
q is 1 or 2;
r is 0 or 1;
In this case, the sum of m, n, p, q and r is at least 2;
R1 is hydrogen, methyl, F, Cl, -OR (7 ), - NR (8) R (9) or be -CF _3;
R (7) is methyl, CF ₃ or CH ₂ -CF _3;
R (8) and R (9) independently of one another are hydrogen, methyl or CH ₂ -CF _3;
R2 is hydrogen, F or Cl;
R3 is an CF _{_3,} SO ₂ CH ₃ or SO ₂ NH _2;
R4 is hydrogen;
3. A compound of formula I as defined in claim 1 or 2, and a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen or F.

A compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 for use as a medicament.

Of arrhythmia, life-threatening cardiac ventricular fibrillation, myocardial infarction for the treatment or prevention of acute or chronic damage, injury or indirect sequelae of organs and tissues caused by ischemic or reperfusion events Shock, for the treatment or prevention of cardiac ischemia, peripheral and central nervous system ischemia or stroke or peripheral organs and tissues ischemia for the treatment or prevention of angina Hypertension, in particular of disease, of disease, where cell proliferation represents a primary or secondary cause, cancer, metastasis, prostatic hyperplasia or prostatic hyperplasia, atherosclerosis or lipid metabolism defects Essential hypertension, disorders of the central nervous system, especially those caused by CNS (central nervous system) hyperexcitability such as epilepsy or central convulsions, disorders of the central nervous system, especially anxiety, depression or Spirit Internal for the treatment or prevention of non-insulin dependent diabetes mellitus (NIDDM) or late diabetes disorders, thrombotic, disorders caused by endothelial dysfunction, intermittent claudication for the treatment or prevention of diseases Caused by protozoa of heart failure or congestive heart failure, acute or chronic inflammatory disorders for the treatment or prevention of organ fibrosis, liver fibrosis, kidney fibrosis, vascular fibrosis and cardiac fibrosis For the treatment and prevention of malaria and poultry coccidiosis and for the preservation and recovery of transplanted organs for surgical treatment, for use in surgery and organ transplantation For the treatment and alleviation of cardiotoxic effects in thyroid poisoning to prevent aging or prolong life in the manufacture of drugs to prevent change Use of a compound or a pharmaceutically acceptable salts in the formula I as claimed in any one of claims 1 to 3 in the or diagnostic aid for Preparation of things.

Of arrhythmia, life-threatening cardiac ventricular fibrillation, myocardial infarction for the treatment or prevention of acute or chronic damage, injury or indirect sequelae of organs and tissues caused by ischemic or reperfusion events Shock, for the treatment or prevention of cardiac ischemia, peripheral and central nervous system ischemia or stroke or peripheral organs and tissues ischemia for the treatment or prevention of angina Hypertension, in particular of disease, of disease, where cell proliferation represents a primary or secondary cause, cancer, metastasis, prostatic hyperplasia or prostatic hyperplasia, atherosclerosis or lipid metabolism defects Essential hypertension, disorders of the central nervous system, especially those caused by CNS (central nervous system) hyperexcitability such as epilepsy or central convulsions, disorders of the central nervous system, especially anxiety, depression or Spirit Internal for the treatment or prevention of non-insulin dependent diabetes mellitus (NIDDM) or late diabetes disorders, thrombotic, disorders caused by endothelial dysfunction, intermittent claudication for the treatment or prevention of diseases Caused by protozoa of heart failure or congestive heart failure, acute or chronic inflammatory disorders for the treatment or prevention of organ fibrosis, liver fibrosis, kidney fibrosis, vascular fibrosis and cardiac fibrosis For the treatment and prevention of malaria and poultry coccidiosis and for the preservation and recovery of transplanted organs for surgical treatment, for use in surgery and organ transplantation For the treatment and alleviation of cardiotoxic effects in thyroid poisoning to prevent aging or prolong life in the manufacture of drugs to prevent change Use of other drugs or active ingredients in combination with compounds or their pharmaceutically acceptable salts of formula I according to any one of claims 1 to 3 in the or diagnostic aid for Preparation of things.

Use of a compound of formula I according to claim 6 or a pharmaceutically acceptable salt thereof in combination with a cardiotoxic and cytotoxic drug or active ingredient in the manufacture of a drug having reduced cardiotoxic and cytotoxic properties .

Alone or other drugs or active ingredients in the manufacture of a medicament for the treatment or prevention of acute and chronic defects, disorders or indirect secondary disorders of organs and limbs caused by ischemic events or by reperfusion events Use of a compound of formula I or a pharmaceutically acceptable salt thereof according to claim 5 or 6 in combination with.

7. A compound of formula I according to claim 5 or 6 or a pharmaceutically acceptable thereof, alone or in combination with other drugs or active ingredients in the manufacture of a medicament for the treatment of life-threatening cardiac ventricular fibrillation Salt used.

Use of a compound of formula I or a pharmaceutically acceptable salt thereof according to claim 5 or 6 alone or in combination with other drugs or active ingredients in the manufacture of a medicament for the treatment or prevention of metastases .

7. A compound of formula I according to claim 5 or 6 alone or in combination with other drugs or active ingredients in the manufacture of a medicament for the treatment or prevention of fibrotic heart disease, heart failure or congestive heart failure Use of their pharmaceutically acceptable salts.

A human comprising an effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 together with pharmaceutically acceptable carriers and additives. Drug for use in animal or plant protection.

4. At least one compound of formula I according to any one of claims 1 to 3 or a combination thereof together with pharmaceutically acceptable carriers and additives in combination with other pharmacologically active ingredients or drugs. An agent for use in human, animal or plant protection comprising an effective amount of a pharmaceutically acceptable salt.